Topical drug delivery using phosphatidylcholine

ABSTRACT

The present invention relates to compositions and methods for transdermal drug delivery comprising formulating a phosphatidylcholine carrier composition containing the drug and applying the composition to the skin.

PRIOR APPLICATION

[0001] Applicant claims priority benefits under 35 U.S.C. §119(e) ofU.S. Provisional Patent Application Serial No. 60/384,597 filed May 31,2002.

FIELD OF THE INVENTION

[0002] The present invention relates to a topical drug deliverycomposition and method. More specifically, this invention relates totopical drug delivery compositions and methods usingphosphatidylcholine.

BACKGROUND OF THE INVENTION

[0003] Transdermal drug delivery systems may be designed to act locallyat the point of application or to act systemically by entering thebody's blood circulation. In these systems, delivery may be achieved bydirect topical application of a substance or drug in the form of anointment or the like, or by adhesion of a patch with a reservoir thatholds the drug and releases it to the skin in a time-controlled fashion.

[0004] Transdermal delivery systems for agents such as drugs, painrelieving compounds, vitamins, and skin improving compounds have been inuse for a number of years. However, these systems have typically onlybeen useful for transdermal delivery of relatively small molecules. Theskin's porous structure permits such small molecules to pass from theepidermis to the dermis via diffusion. These transdermal deliverysystems such as creams have been developed for use with analgesics andskin refining compounds. Transdermal systems using a patch have beendeveloped for nicotine and estrogen therapies. Estradiol technologiesare described in U.S. Pat. No. 6,521,250 to Meconi, et al.. However,large molecules, such as insulin, are not able to diffuse through theskin. To date there has not been an effective and economical method totransport such molecules through the epidermis to enter the bloodstreamvia the dermal vasculature.

[0005] It has been proposed that molecules, potentially including largermolecules, can be transported through the skin when such molecules arecontained within spherical vesicles, variously called microparticles,microspheres, liposomes, lipid vesicles, transfersomes, formed byhydrating a phospholipid. The resulting vessels are water-insoluble andare dispersed and suspended in a liquid base material which is appliedto the skin to deliver the drug. U.S. Pat. No. 6,165,500 to Cevcdiscloses “transfersomes,” which are vesicles containing both a lipidand surfactant, to achieve transdermal delivery, based on a theory thatosmotic pressure will drive the transfersomes through the dermis. Othersolutions have been proposed, including the use of ultrasound devices togenerating shock waves to enlarge pores, use of electric current todrive substances across skin, and the use of microneedles to pierce skinand deliver drugs into bloodstream. (See More Than the Patch: New Waysto Take Medicine Via Skin, New York Times, Jul. 2, 2002, page F5.

[0006] There remains a need for a transdermal drug delivery system withthe improved skin permeability and ability to transport a wider range ofsubstances or drugs. This problem is particularly apparent in thetransdermal delivery of substances composed of large molecules, such aspolypeptides or proteins, which do not readily pass through the pores ofthe skin. Absent such a transdermal drug delivery system, the use ofinjections to deliver these substances will remain the conventionaldosage method, despite the pain, complicated administration and generalinvasiveness involved therein.

SUMMARY OF THE INVENTION

[0007] The present invention relates to compositions and methods oftransdermal drug delivery comprising formulating a compositioncontaining the drug in a crystallized phosphatidylcholine carrier andapplying the composition to the skin.

DETAILED DESCRIPTION

[0008] Phosphatidylcholine is used as a carrier for the topical drugdelivery of macromolecules in the practice of this invention.Phosphatidylcholine is a basic component of cell membrane bilayers andthe main phospholipid circulating in the plasma. Phosphatidylcholine ishighly absorbable and supplies choline which is needed to facilitatemovement of fats and oils across and maintain cell membranes in animals.

[0009] Phosphatidylcholine compositions (herein abbreviated “PCcompositions”) of the present invention are formulated to containmacromolecules soluble in PC, which are then applied to skin fortransdermal delivery of the macromolecule. PC compositions of theinvention are efficacious in the delivery of macromolecular drugs thatare conventionally administered intramuscularly, intravenously ororally, including, but not limited to polypeptides such as insulin andsomatropin, prostaglandins, glucocorticoids, estrogens, androgens, andthe like.

[0010] It is an advantage of the invention that topical delivery iseasier and pleasanter as an administration route than injections,particularly for drugs such as insulin that must be given to patientsover a period of time, or for a lifetime. Furthermore, unlike oraladministration where a substantial amount of the drug can be destroyedin the digestive process, the drugs in a topical application are notwasted. Topical application allows a steady diffusion of the drug to thedesired target area without the cyclic dosages typical of orally orparenterally administered drugs.

[0011] Typical phosphatidylcholine compositions of the present inventionare nonpolar and contain about 85% phosphatidylcholine. By“phosphatidylcholine” is meant a mixture of stearic, palmitic, and oleicacid diglycerides linked to the choline ester of phosphoric acid,commonly called lecithin. Many commercial lecithin products areavailable, such as, for example, Lecithol®, Vitellin®, Kelecin®, andGranulestin® because lecithin is widely used in the food industry.Compositions of the invention can contain synthetic or natural lecithin,or mixtures thereof. Natural preparations are preferred because theyexhibit desirable physical characteristics and are both economical andnontoxic.

[0012] The macromolecular drugs are mixed with the PC composition underconditions to become entrapped in a phosphatidylcholine bilayer.Phosphatidylcholine forms a bilayer entrapping the macromolecular drug,which may be a polypeptide, contributing to the stability of the activemolecule and enhancing penetration. The PC composition therein comprisesa carrier-drug combination to be applied topically.

[0013] While not wishing to be bound by any particular theory, it isbelieved that the following mechanism illustrates how the PC compositionacts to efficiently transport the drug across the epidermis, maximizingpenetration of the drug. The PC composition, in liquid crystal phase, isloosely arranged in multilamellar fashion, with the drug being bondedand entrapped within the lipid bilayers formed by the PC composition.This forms a loosely arranged, yet stable, PC composition carrier-drugcomplex. When placed on the epidermis, the carrier-drug complex beginsto diffuse through the epidermis. The phosphatidylcholine molecularchain remains loosely linked with the drug molecular chain and thediffusing phosphatidylcholine molecules“drag” the drug molecules alongas they pass through the skin layers. Moreover, the phosphatidylcholinemolecules may begin to separate from the loosely arranged carrier-drugcomplex and become integrated into the dermis. As thephosphatidylcholine molecules separate from the crystallizedphophoslipid bilayer structure of the carrier-drug complex the drugmolecules are released. As these drug molecules are released, they arenow within into the dermis and may enter the dermal vasculature so theymay act accordingly in the bloodstream. Drug molecules which were oncetoo large to diffuse, by themselves, into the pores of the epidermis,have instead been forced through the epidermis by phosphatidylcholinecarriers which naturally enter and integrate into lipid bilayerstructures within the cells of the epidermis and/or dermis andresultantly are required to release their bonds to the drug moleculesand set them free within the dermis.

[0014] Preferred PC compositions comprise phosphatidylcholine in crystalphase to increase fluidity of the lipid bilayer formed. By reducingrigidity and loosening the phospholipid bilayer of the PC composition,larger molecules may embed therein and penetration of the carrier-drugcomposition by the cell membrane is facilitated. The skin is morepermeable to the fluid, less structured lipid bilayer of thePC/carrier-drug composition applied thereon than to the drug by itself,or entrapped in an organized, arranged vesicle such as a liposome. Theloosely packed lipid bilayer of the crystallized carrier-drugcomposition integrates into the cell membrane, and as a result, hastransported the drug so it can enter the bloodstream to act upon thebody. The PC composition may be a multilamellar liquid crystal phase ora liquid crystal phase suspension in water which may be converted tomultilamellar liquid lipid vesicles.

[0015] In preferred embodiments, nonpolar preparations ofphosphatidylcholine are formulated to contain adjunct ingredients, e.g.,lipoic acid and ascorbyl palmitate, in addition to the macromoleculardrug. The adjunct ingredients act synergistically to help to minimizedegradation and thus preserve the integrity of the insulin polypeptidechains, and to enhance transdermal penetration of active insulin so thatit can be absorbed by the dermal vasculature.

[0016] Preferred PC compositions of the invention contain somepolyenylphosphatidylcholine (herein abbreviated “PPC”) to enhanceepidermal penetration. By “polyenylphosphatidylcholine” is meant anyphosphatidylcholine bearing two fatty acid substituents, wherein atleast one is an unsaturated fatty acid with at least two double bondssuch as linoleic acid. Preferred PPCs contain a mixture of substitutentssuch as those found in natural products such as soybean lecithin, whichcontains 11.7% palmitic, 4.0% stearic, 8.6% palmitoleic, 9.8% oleic,55.0% linoleic, and 4.0% linolenic acid substituents and is a by-productof soybean oil manufacture.

[0017] Certain types of soybean lecithin, for example, contain higherlevels of polyenylphosphatidylcholine, withdilinoleoylphosphatidylcholine (18:2-18:2 phosphatidylcholine) as themost abundant phosphatidylcholine species, than conventional food gradelecithin, and are useful in formulating phosphatidylcholine insulincompositions of the invention. Alternatively, conventional soybeanlecithin is enriched with PPC by adding soybean extracts containing highlevels of PPC. As used herein, this type of phosphatidylcholine iscalled “PPC-enriched” phosphatidylcholine, even where the termencompasses lecithin obtained from natural sources exhibiting PPC levelshigher than ordinary soybean varieties. These products are commerciallyavailable from American Lecithin, Rhône-Poulenc and other lecithinvendors. American Lecithin markets its products with a “U” designation,indicating high levels of unsaturation; Rhône-Poulenc's product is asoybean extract containing about 42% dilinoleoylphosphatidylcholine andabout 24% palmitoyllinoleylphosphatidylcholine (16:0-18:2 PC) as themajor PC components.

[0018] PC compositions are used for transdermal polypeptide delivery insome preferred embodiments. Polypeptide drugs that are deliveredtransdermally using formulations can be small, e.g., ocytocin andvasopressin nonapeptides or large, e.g., insulin, gonadotropin, andsomatropin. PC compositions of the invention deliver drugs including,but are not limited to, oxytocin, vasopressin, insulin, somatotropin,calcitonin, chorionic gonadotropin, menotropins, follitropins,somatostatins, progestins, and combinations of any of these. These drugsare readily available from a variety of commercial sources. Insulin, forexample, is marketed under the tradenames Humulin®, Novolin®, Humalog®,and Inutral®. Somatotropin is marketed under the tradenames Gentropin®,Humatrope®, Nutropin®, and Serostim®. Some of these products and otherpolypeptides contain porcine sequences. Preferable compositions of theinvention are preferably formulated with recombinant human polypeptides.It is an advantage of the invention that PC insulin compositions areformulated with commercially available ingredients.

[0019] One, non-limiting, example of an insulin topical preparation wasformulated by combining 0.75% methyl paraben with a commercialphosphatidylcholine preparation marketed as a solution denoted NAT-8729(containing PEG-400 at 40% and P.G. at 5%) by mixing for an hour or moreto emulsify. To this is slowly added Dow Corning Fluid 200-5 or 10 cst(1% by weight), the formulation is mixed, and then Dow Corning Fluid 190(1% by weight) is slowly added, and the formulation is further mixed toprovide a stock insulin carrier. Prior to topical administration,insulin is added at a level of about 3.8 mg/ml to provide about 100insulin units per ml.

[0020] Another, non-limiting, example of a pituitary growth hormone(somatotropin) composition was formulated with 85% phosphatidylcholineto which lipoic acid and ascorbyl palmitate was added as antioxidants.Somatotropin readily dispersed in phosphatidylcholine and remainedstable in it. Growth hormone appeared to penetrate the skin well whenthe composition was topically applied.

[0021] It is appreciated that the foregoing is illustrative and notlimiting of the invention, and that various changes and modifications tothe preferred embodiments described above will be apparent to thoseskilled in the art. Such changes and modifications can be made withoutdeparting from the spirit and scope of the present invention, and it istherefore intended that such changes and modification be covered by thefollowing claims.

What is claimed is:
 1. A composition comprising crystallizedphosphatidylcholine and drug molecules entrapped within saidphosphatidylcholine.
 2. A composition of claim 1, wherein the drugmolecules comprise polypeptides.
 3. The composition of claim 1 whereinthe drug molecules are selected from the group consisting of oxytocin,vasopressin, insulin, somatotropin, calcitonin, chorionic gonadotropin,menotropins, follitropins, somatostatins, progestins, and combinationsof any of these.
 4. The composition of claim 1 wherein the compositioncontains about 85% phosphatidylcholine.
 5. The composition of claim 1wherein the phosphatidylcholine is soybean lecithin.
 6. The compositionof claim 1, 2, 3, or 4 further comprising polyenylphosphatidylcholine.7. The composition of claims 1, 2, 3, 4 or 5 further comprising one ormore of ascorbyl palmitate and lipoic acid.
 8. A method for topicallyadministering a macromolecular drug comprising formulating a compositioncontaining the drug in a non-polar or crystal phosphatidylcholinecarrier and applying the composition to the skin.
 9. A method accordingto claim 8 wherein the composition contains about 85%phosphatidylcholine.
 10. A method according to claims 8 or 9 wherein thephosphatidylcholine is soybean lecithin.
 11. A method according toclaims 8, 9, or 10 wherein the phosphatidylcholine containspolyenylphosphatidylcholine.
 12. A method according to claim 8 whereinthe macromolecular drug is a polypeptide.
 13. A method according toclaim 12 wherein the polypeptide is selected from the group consistingof oxytocin, vasopressin, insulin, somatotropin, calcitonin, chorionicgonadotropin, menotropins, follitropins, somatostatins, progestins, andcombinations of any of these.
 14. A method according to claim 12 whereinthe polypeptide is somatotropin.
 15. A method according to claim 12wherein the polypeptide is insulin.
 16. A method for administeringinsulin to a patient comprising topically applying a compositioncomprising a crystal or non-polar phosphatidylcholine carrier andinsulin to skin of the patient.
 17. The method of claim 16, wherein thephosphatidylcholine carrier comprises about 85% phosphatidylcholine. 18.A method according to claims 17 wherein the phosphatidylcholine carriercontains polyenylphosphatidylcholine.